Many cyclic peptides have potent antibacterial activities. For instance, daptomycin is a cyclic lipodepsipeptide consisting of 13 amino acids, 10 of which make up a 31-membered ring and 3 are anchored as an exocyclic tail with the N-terminal n-decanoyl lipid. Within this structure are two unnatural amino acids, kynurenine (Kyn) and 3-methyl-glutamic acid (3-mGlu), as well as three D amino acids (i.e., D-Asn, D-Ala and D-Ser). Functionally, this compound exhibits a unique mode of action which is significantly different from that of other currently used antibiotics: it first undergoes a conformational change upon binding to Ca2+ ions, so that the entire structure can be inserted into bacterial membranes via the lipid tail, which then induces membrane leakage and cell death.
Efforts have previously been made by various research groups to establish the structure-activity relationship (SAR) of daptomycin and produce it analogues. However, since daptomycin can only be produced by fermentation, only a limited number of daptomycin analogues with few structural variations could be generated via genetic engineering of the non-ribosomal peptide synthetase in the daptomycin biosynthetic pathway, and by chemoenzymatic and semisynthesis approaches. These analogues are limited to swapping natural amino acids. None of these daptomycin analogues have shown better antibacterial activities than the parent daptomycin.
Indeed, these abovementioned approaches cannot generate analogues modifying at position Trp1, Thr4, Gly5 and Kyn13, and cannot introduce unnatural amino acids.